1. Field of the Invention
This invention relates to novel platinum(II) complexes having antitumor activity. More particularly, it relates to novel antitumor platinum(II) complexes of 1,2-diaminocyclohexane, 1-aminomethylcyclooctylamine and 1,2-diamino-2,4-dimethylpentane.
2. Description of the Prior Art
Various platinum(II) complexes of 1,2-diaminocyclohexane, 1-aminomethylcyclooctylamine and 1,2-diamino-2,4-dimethylpentane have been disclosed in the scientific and patent literature as having antitumor activity.
With respect to platinum(II) complexes of 1,2-diaminocyclohexane, the original antitumor complex appears to have been dichloro(1,2-diaminocyclohexane)platinum(II) reported, for example, in Bioinorg. Chem. 2: 187-210 (1973). The chloride ligands in this complex were then replaced by various inorganic and organic ligands such as nitrato, methanesulfonato, tartrato, sulfato, methylmalonato, orthophosphato, acetylacetonato, pyruvato, phthalato, oxalato, glycerophosphato, gluconato, glycerato, etc. (see, for example, Cancer Treat. Rep. 61(8): 1519-1525 (1977). These and other analogs are disclosed in U.S. Pat. No. 4,169,846, J. Med. Chem. 21(12): 1315-1318 (1978), J. Clin. Hematol. Oncol. 7(4): 867-876 (1977)-see bis(monobromoacetato) analog, J. Clin. Hematol. Oncol. 7(1): 231-241 (1977); U.K. Patent application No. 2,003,468A-see 4 carboxyphthalato analog, J. Clin. Hematol. Oncol. 7(1): 220-230 (1977)-see analogs of ligands such as ketomalonate, 1,2-dibromomaleate, 1,2-dibromosuccinate, J. Clin. Hematol. Oncol. 8(2 ): 44-50 (1978)-note disclosure of analog of the formula ##STR1## U.S. Pat. No. 4,115,418, U.S. Pat. No. 4,256,652 and U.S. Pat. No. 4,284,579-note preparation of cis-dihydroxy(1,2-diaminocyclohexane)platinum(II) and analog with N-phosphonoacetyl-L-aspartato ligand.
J. Inorg. Biochem. 11: 139-149 (1979) discloses preparation of 1-aminomethylcyclooctylamine and 1,2-diamino-2,4-dimethylpentane (starting material for certain complexes of the present invention) as well as complexes of such amine ligands with ligands such as Cl.sup.-, SO.sub.4.sup.=, CH.sub.3 (COO.sup.-).sub.2 and (BrCH.sub.2 COO.sup.-).sub.2.
U.S. Pat. No. 4,359,425 discloses antitumor organoplatinum complexes of the general formula ##STR2## wherein X and Y each or taken together represent a mono- or bi-functional ligand selected from the group consisting of halogenato, nitrato, sulfonato, monocarboxylato, sulfato and dicarboxylato and each of n and m is an integer of 1 or 2.
European Patent Application No. 55,300 discloses as antitumor agents platinum(II) complexes of the formula ##STR3## wherein --B--B-- represents ##STR4## in which R.sub.1 and R.sub.2 are the same or different and each is hydrogen, an alkyl group or an aryl group, and n, m and l are O or an integer of from 1 to 3, at least one of A.sub.1 and A.sub.2 is ##STR5## and the other is the ligand of D-gluconic acid, Cl.sup.-, Br.sup.-, I.sup.-, F.sup.-, XCH.sub.2 COO.sup.- (in which X is a halogen atom), NO.sub.3.sup.-, SO.sub.4.sup.-2, H.sub.2 PO.sub.4.sup.- or H.sub.2 O or, when taken together, A.sub.1 and A.sub.2 may form a ring together with Pt(II), in the latter case --A.sub.1 --A.sub.2 -- being the ligand of D-gluconic acid.
U.K. Patent Application No. 2,093,845 discloses as antitumor agents platinum(II) complexes of the formula ##STR6## wherein either R.sub.1 and R.sub.2 independently are hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, aryl or aralkyl group or R.sub.1 and R.sub.2 when taken together may be a substituted or unsubstituted cycloalkyl group, R.sub.3 and R.sub.4 are each independently hydrogen or a substituted or unsubstituted alkyl, aryl or aralkyl group and X is a chlorine, bromine or iodine atom, a sulfate radical, a substituted or unsubstituted carboxylate radical and Y independently from X is a chlorine, bromine or iodine atom, a hydroxyl group, a nitrate group or a carboxylate group.
U.K. Patent Application No. 2,024,823A discloses as antitumor agents platinum(II) complexes of the formula ##STR7## in which R.sub.1 and R.sub.2 are each independently a hydrogen atom or an optionally substituted alkyl, cycloalkyl, aryl or aralkyl group, or R.sub.1 and R.sub.2 together are an optionally substituted cycloalkyl group, R.sub.3 and R.sub.4 are each independently a hydrogen atom or an optionally substituted alkyl, aryl or aralkyl group, and X is an anionic group.
The amine ligand 1,2-diaminocyclohexane may be used as a mixture of cis-, trans-d-and trans-l-isomers to produce the corresponding isomer mixture derived from such starting material. Alternatively and preferably, the 1,2-diaminocyclohexane may be separated into the individual cis-, trans-d- and trans-l-isomers by the procedure described, for example, in U.S. Pat. No. 4,169,846. While all of these individual isomers may be utilized to prepare the complexes of the present invention, the preferred starting material is the trans-l-isomer, hereinafter referred to below as the trans(-)-isomer. This isomer has previously been reported to confer the highest activity in other 1,2-diaminocyclohexane platinum(II) complexes (see, for example, Gann 67: 921-922, 1976 and J. Clin. Hematol. Oncol. 8(2): 44-50, 1978).
While a large number of platinum(II) complexes have been disclosed as having some antitumor activity, there remains a need for new platinum(II) complexes which will have more advantageous properties, i.e. greater activity, broader spectrum, less toxicity, etc. Especially desirable are platinum complexes having significant advantages over cisplatin, the only platinum complex presently being marketed as an anticancer agent.